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Transforming growth factor α‐induced expression of type‐1 plasminogen activator inhibitor in astrocytes rescues neurons from excitotoxicity
Author(s) -
Gabriel Cecília,
Ali Carine,
Lesné Sylvain,
FernándezMonreal Mónica,
Docagne Fabian,
Plawinski Laurent,
MacKenzie Eric T.,
Buisson Alain,
Vivien Denis
Publication year - 2003
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.02-0403fje
Subject(s) - excitotoxicity , neuroprotection , mapk/erk pathway , nmda receptor , transforming growth factor , plasminogen activator , astrocyte , microbiology and biotechnology , activator (genetics) , chemistry , signal transduction , biology , neuroscience , endocrinology , receptor , central nervous system , biochemistry
Although transforming growth factor (TGF)‐α, a member of the epidermal growth factor (EGF) family, has been shown to protect neurons against excitotoxic and ischemic brain injuries, its mechanism of action remains unknown. In the present study, we used in vitro models of apoptotic or necrotic paradigms demonstrating that TGF‐α rescues neurons from N‐methyl‐ d ‐aspartate (NMDA)‐induced excitotoxic death, with the obligatory presence of astrocytes. Because neuronal tissue‐type plasminogen activator (t‐PA) release was shown to potentiate NMDA‐induced excitotoxicity, we observed that TGF‐α treatment reduced NMDA‐induced increase of t‐PA activity in mixed cultures of neurons and astrocytes. In addition, we showed that although TGF‐α induces activation of the extracellular signalregulated kinases (ERKs) in astrocytes, it failed to activate p42/p44 in neurons. Finally, we showed that TGF‐α, by an ERK‐dependent mechanism, stimulates the astrocytic expression of PAI‐1, a t‐PA inhibitor, which mediates the neuroprotective activity of TGF‐α against NMDA‐mediated excitotoxic neuronal death. Taken together, we indicate that TGF‐α rescues neurons from NMDA‐induced excitotoxicity in mixed cultures through inhibition of t‐PA activity, involving PAI‐1 overexpression by an ERK‐dependent pathway in astrocytes.